Acute Response in the Noninfarcted Myocardium Predicts Long-Term Major Adverse Cardiac Events After STEMI

Background Acute ST-segment elevation myocardial infarction (STEMI) has effects on the myocardium beyond the immediate infarcted territory. However, pathophysiologic changes in the noninfarcted myocardium and their prognostic implications remain unclear. Objectives The purpose of this study was to evaluate the long-term prognostic value of acute changes in both infarcted and noninfarcted myocardium post-STEMI. Methods Patients with acute STEMI undergoing primary percutaneous coronary intervention underwent evaluation with blood biomarkers and cardiac magnetic resonance (CMR) at 2 days and 6 months, with long-term follow-up for major adverse cardiac events (MACE). A comprehensive CMR protocol included cine, T2-weighted, T2∗, T1-mapping, and late gadolinium enhancement (LGE) imaging. Areas without LGE were defined as noninfarcted myocardium. MACE was a composite of cardiac death, sustained ventricular arrhythmia, and new-onset heart failure. Results Twenty-two of 219 patients (10%) experienced an MACE at a median of 4 years (IQR: 2.5-6.0 years); 152 patients returned for the 6-month visit. High T1 (>1250 ms) in the noninfarcted myocardium was associated with lower left ventricular ejection fraction (LVEF) (51% ± 8% vs 55% ± 9%; P = 0.002) and higher NT-pro-BNP levels (290 pg/L [IQR: 103-523 pg/L] vs 170 pg/L [IQR: 61-312 pg/L]; P = 0.008) at 6 months and a 2.5-fold (IQR: 1.03-6.20) increased risk of MACE (2.53 [IQR: 1.03-6.22]), compared with patients with normal T1 in the noninfarcted myocardium (P = 0.042). A lower T1 (<1,300 ms) in the infarcted myocardium was associated with increased MACE (3.11 [IQR: 1.19-8.13]; P = 0.020). Both noninfarct and infarct T1 were independent predictors of MACE (both P = 0.001) and significantly improved risk prediction beyond LVEF, infarct size, and microvascular obstruction (C-statistic: 0.67 ± 0.07 vs 0.76 ± 0.06, net-reclassification index: 40% [IQR: 12%-64%]; P = 0.007). Conclusions The acute responses post-STEMI in both infarcted and noninfarcted myocardium are independent incremental predictors of long-term MACE. These insights may provide new opportunities for treatment and risk stratification in STEMI.

S urvival rate after acute ST-segment elevation myocardial infarction (STEMI) has dramatically improved in recent times through primary percutaneous coronary intervention (PPCI) and optimal medical therapy. 1 However, some patients experience poor long-term cardiovascular outcomes, such as heart failure, arrhythmias, and cardiac death. 1 Thus, early identification of predictors of such adverse outcomes is desirable to improve long-term prognosis after STEMI.
The degree of acute injury to the infarcted myocardium, such as infarct size (IS), or the presence of microvascular obstruction (MVO), and intramyocardial hemorrhage (IMH), is a known independent predictor of both short-and long-term clinical outcomes post-STEMI. 2 The noninfarcted myocardium includes the salvaged area at risk (AAR) and the remote zone farthest away from the infarction (Central Illustration). Emerging translational and clinical evidence suggests that the noninfarcted remote myocardium may also exhibit acute inflammation and injury post myocardial infarction (MI). [3][4][5][6][7] These acute pathophysiologic changes are thought to be mediated by the innate immune response 3,4 and may lead to maladaptive matrix changes, resulting in adverse left ventricular (LV) remodeling and poor long-term outcomes. [7][8][9] Characterization of the noninfarcted myocardium immediately post-STEMI may therefore help to improve risk stratification and identify therapeutic targets for cardio-protection against heart failure.

Multiparametric cardiac magnetic resonance (CMR)
imaging is a powerful noninvasive tool to interrogate myocardial tissue after STEMI. 2 Advanced CMR techniques, such as T1-mapping, are highly sensitive for detecting increased free water content in acute myocardial injury, particularly MI. [10][11][12] Elevated T1 values can delineate the edematous AAR 13 and predict the final IS post-STEMI. 14 Lowered T1 in the core of the infarct, thought to reflect MVO and/or IMH, is inversely associated with short-term negative remodeling of the LV and long-term adverse outcomes. 15 In the noninfarcted remote myocardium, elevated T1 is associated with negative remodeling of the LV and adverse outcomes in patients at 6 months after STEMI. 6,7 Thus, changes in the noninfarcted myocardium may also carry important clinical significance; however, their long-term prognostic relevance is unclear.
In this study, we hypothesized that, in addition to changes in the infarcted myocardium, the noninfarcted myocardium may also demonstrate various grades of acute response immediately post-STEMI. We sought to detect these changes noninvasively using CMR and to determine whether these changes may predict long-term major adverse cardiac events (MACE).

METHODS STUDY
POPULATION AND TREATMENT.
Patients with STEMI admitted to our center for PPCI were prospectively enrolled in the OxAMI (Oxford Acute Myocardial Infarction) study ( Figure 1). 16,17 The study protocol was approved by the local ethics committee  Values are mean AE SD, %, or median (IQR), unless otherwise indicated.
Significant adverse remodeling is defined as $20% increase in LVEDV. Values in bold indicate a value of P < 0.05.

DISCUSSION
Our study is the first to assess the long-term prognostic value of the acute changes in both the noninfarcted and infarcted myocardium immediately after STEMI. Our novel contributions are as follows:  Figure 3). Infarct T1 indices offered significant improvement in risk prediction beyond conventional markers, such as IS and presence of MVO ( Table 5, Supplemental Table 2).
More interestingly, beyond the infarcted territory, remote myocardial injury and dysfunction post-MI have been described in animal and human studies. [3][4][5][6][7][8] The proposed mechanisms include activation of the innate immune system and inflammation. 4 Remote myocardial inflammation is believed to be mediated mainly by a 5-to 6-fold increase in leukocytes, and is coupled with an upregulation of inflammatory mediators including cytokines, adhesion molecules, and matrix metalloproteinases. 3,4 These may result in adverse LV remodeling, fibrosis, and systolic dysfunction. 8 Increased remote myocardial T1 post-STEMI is known to be associated with adverse short-term outcomes, which we have also confirmed in this study, but its long-term prognostic implication had remained unclear. 6,7 We have now shown that although the remote myocardial T1 is weakly associated with long-term MACE, a more complete assessment of the entire noninfarcted myocardium with T1-mapping provides a more powerful and independent prediction of long-term MACE ( Tables 4 and 5, Supplemental Table 2). In particular, for every 10-ms increase in noninfarct myocardial T1, the risk of long-term MACE increased by 9%. This suggests that the assessment of just a small remote zone of the noninfarcted myocardium is less comprehensive.
Equally, neither the acute IS nor AAR (which relies on the assumption that remote myocardium is normal) Abbreviations as in Table 2.
Shanmuganathan et al were independent predictors of MACE in multivariate Cox regression models containing the noninfarct and infarct T1.
An acutely high remote T1 may be a surrogate marker for a large insult to the LV myocardium in STEMI. In our study, the abnormal response in the noninfarcted myocardium was associated more frequently with left anterior descending coronary artery infarctions, larger acute IS, and higher peak troponin level (Tables 1 and 2). Multivessel disease was not a predictor of clinical outcomes and, more interestingly, was more prevalent among those with normal noninfarct T1 than in those with high noninfarct T1 (37% vs 23%; P ¼ 0.028). Thus, it is unlikely that resting ischemia from nonculprit vessels contributed significantly to the severe elevation observed in the noninfarcted myocardium.
Although the fraction of global myocardium with high T1 is positively correlated with inflammatory biomarkers, only remote T1 showed weak relationship with neutrophil counts and trend correlations with monocytes and C-reactive protein level post PPCI (Supplemental Table 6). The lack of correlations within either the infarct and noninfarct tissue T1 is likely caused by the heterogeneity of these tissue classes characterized by various competing mechanisms affecting the measured T1 (eg, MVO core in the infarcted area). In contrast, the remote myocardium T1 changes were found to be a better overall indicator of the systemic inflammatory burden. This is in keeping with preclinical and clinical observations that remote myocardial injury is related to the ischemic insult and the ensuing immune response and inflammation. 3,4,7,22 The novelty of establishing the prognostic power of noninfarcted myocardial injury is best seen in the multivariate Cox regression analysis. In all the models consisting of conventional CMR indices (LVEF, IS, MVO), noninfarct myocardial T1 was an independent predictor of outcomes ( Table 5, Supplemental Table 2). Indeed, when the models include both infarct and noninfarct myocardial T1, the performance of CMR in predicting adverse outcomes improved significantly ( Our new findings build on previous reports of an association between remote myocardial changes after  STEMI and adverse LV remodeling and the expansion of extracellular matrix at short-term follow-up, 6,7,9 and demonstrate a strong association with the development of heart failure at long-term. Interestingly in our study, although the significantly abnormal T1 values in either infarcted or noninfarcted territories immediately after STEMI predicted the development of heart failure at long-term, they were not associated with adverse LV remodeling at 6 months (  Table 7). However, some degree of collinearity between the CMR variables in these models may reduce the accuracy of our findings and thus reproducibility studies with larger sample sizes and longer follow-up are needed. It is impossible to exactly match LGE and T1 images; however, to minimize the differences, T1-maps and LGE images were obtained at the same slice position in the scanner and analyzed by experienced operators.
Noninfarcted myocardium, defined as the area without LGE, includes both the salvageable myocardium as well as the myocardium supplied by nonculprit arteries. We did not differentiate the T1 changes in these 2 compartments for 2 reasons. First, it is impossible to accurately delineate the true myocardial area subtended by a coronary artery.
Second, because we observed that the remote T1 is elevated and is associated with outcomes, the derivation of AAR assuming a normal remote region is prone to errors. The exact pathophysiology behind the alterations in infarct and noninfarct T1 in these patients cannot be ascertained without direct histopathology correlates; however, it is widely considered to represent acute myocardial edema in this setting, likely associated with myocardial necrosis and the resulting inflammation. 11,12,26 Although the calculation of noninfarct T1 requires the manual matching of T1-maps and LGE images, it has the potential to be made fully automated with the use of artificial intelligence in CMR. 27 Our study did not use T2-mapping, which has been shown to detect subtle edema in the remote myocardium post-STEMI, 28 but there is strong evidence that T1-mapping is a suitable alternative to detect myocardial edema. 11 Therefore, it holds much promise in our future attempts to better detect the pan-myocardial injury in STEMI, monitor response to treatment, and offer prognostication.
TRANSLATIONAL OUTLOOK: This study shows that the assessment of injury in both infarcted and noninfarcted myocardium immediately after reperfused STEMI using noncontrast T1-mapping on CMR offers independent and incremental prediction of long-term adverse clinical outcomes, mainly that of new-onset heart failure. It would be desirable to design trials in which patients with significant noninfarct myocardial injury after STEMI are started on optimal medical therapy irrespective of the LVEF to see if it would reduce the risk of heart failure in the long-term.